(NEO-)ADJUVANT THERAPY FOR HER-2+ BREAST CANCER · chemotherapy in this group. However, in small, node-negative tumours, combination of single-agent paclitaxel and trastuzumab provides

esmo.org

(NEO-)ADJUVANT THERAPY FOR HER-2+ BREAST CANCER

Rebecca Dent MD FRCP (Canada)

ASSOCIATE PROFESSOR, DUKE-NUS MEDICAL SCHOOL

HEAD AND SENIOR CONSULTANT, NATIONAL CANCER CENTER

SINGAPORE

Disclosures

• Advisory Boards, Honorariums or Travel

– Astra Zeneca, Eisai, Genentech, Merck, Novartis,

Pfizer, Roche

Introduction of new treatment modalities over time has improved recurrence outcomes in the ADJUVANT setting

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet 2012; 379:432–444;2. EBCTCG. Lancet 2015; 386:1341–1352; 3. EBCTCG. Lancet 2005; 365:1687–1717;

4. Jackisch C, et al. SABCS 2015; Poster PD5-01; 5. Slamon D, et al. SABCS 2015; Oral presentation S5-04;6. Slamon D, et al. N Engl J Med 2011; 365:1273−1283.

AI, aromatase inhibitor;CMF, cyclophosphamide, methotrexate and fluorouracil;HR, hazard ratio; RR, risk ratio.

Consistent & significant benefit

of adjuvant trastuzumab

Four pivotal trials (>12,000 pts) established 18 cycles (1 year) of adjuvant trastuzumab as the SoC for

HER2-positive eBC

1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672;2. Gianni L, et al. Lancet Oncol 2011; 12:236-244;

3. Slamon D, et al. N Engl J Med 2011; 365:1273−1283;4. Perez EA, et al. J Clin Oncol 2011; 29:3366−3373.

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation;SoC, standard of care.

Favours chemo alone0

These adjuvant trials demonstrated consistent DFS and OS benefit with 1 year

of trastuzumab versus observation

1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 2. Smith I, et al. Lancet 2007; 369:29–36;3. Gianni L, et al. Lancet Oncol 2011; 12:236–244; 4. Goldhirsch A, et al. Lancet 2013; 382:1021–1028;

5. Cameron D, et al. Lancet 2017; 389:1195–1205; 6. Slamon D, et al. SABCS 2015; Oral presentation S5-04;7. Romond EH, et al. N Eng J Med 2005; 353:1673–1684; 8. Perez EA, et al. J Clin Oncol 2011; 29:3366–3373;

9. Perez EA, et al. J Clin Oncol 2014; 32:3744–3752; 10. Perez EA, et al. J Clin Oncol 2011; 29:4491–4497.

* Selected from a list of approved regimens consisting of ≥4 cycles.AC, doxorubicin plus cyclophosphamide; CT, chemotherapy;DFS, disease-free survival; FU, follow-up; H, trastuzumab; OS, overall survival;Pac, paclitaxel; RT, radiotherapy; T, docetaxel; TCH, docetaxel, carboplatin.

StudyFU

(yrs) N DFS HR

HERA1–5 1 3387 0.54

CT* ± RT→H(1 year) vs. CT* ± RT

2 3401 0.64

4 3401 0.76

8 3401 0.76

11 3399 0.76

BCIRG 0066

AC→TH vs. AC→TTCH vs. AC→T

10.3 32220.72

0.77

Joint analysis7–9

(NCCTG N9831/NSABP B-31)

2 3351 0.48

3.9 4045 0.52

AC→PacHvs. AC→Pac

8.4 4046 0.60

NCCTG N983110

AC→Pac→H vs. AC→Pac

6 2184 0.67Favours trastuzumab

OS HR

0.66

0.85

0.76

0.74

0.63

0.76

0.61

0.63

0.88Favours trastuzumab Favours chemo alone

SE

QU

EN

TIA

LC

HE

MO

→→ →→H

CO

NC

OM

ITA

NT

CH

EM

O +

H

SE

QU

EN

TIA

LC

HE

MO

→→ →→H

Perez, SABCS 2009

Optimal Chemotherapy regimen? (anthracyclines: to give or not give!)

BCIRG 006 - > can we avoid anthracycline?

Slamon D, et al. SABCS 2015 (Abstract S5-04).MFU, median follow-up

BCIRG 006: DFS final analysis (10.3 years’ MFU)

AC-T AC-TH TCH

74.6%

73.0%

67.9%

0 1 2 3 4 5 6 7 8 9 10 11

Slamon D et al. N Engl J Med 2011;365:1273-1283

Clinical Implications of BCIRG 006

• We don’t know how safe it is to withhold

anthracyclines and in which pts (trial not powered

to show equivalence; trial hypothesis (TCH better)

not proven)

• TCH associated with less cardiotoxicity and less

leukemia (associated with A or C??!!)

• ONLY POSSIBLE CLINICAL RECOMMENDATION:

• TCH is a very good option and should be chosen

when cardiac risk factors or c.i. for anthracyclines

are present

What about duration of trastuzumab?

1 vs. 2 years: HERA

9 weeks: FinHER (Finland)

1 year vs. 3 ms: E 2198 (US)

1 year vs. 9 weeks: ShortHER

1 year vs. 9 weeks: SOLD

1 year vs. 6 ms: PHARE (France)

1 year vs. 6 ms: HeCOG (Greece)

1 year vs. 6 ms: Persephone (UK)

HERA: Longer duration of trastuzumab did

not improve outcomes

Goldhirsch A, et al. Lancet 2013; 382:1021–1028.CI, confidence interval; obs, observation.

62.5%

68.5%

69.3%

64.7%

70.7%

71.2%

70.0%

75.9%

76.4%

1 2 3 4 5 6 7 8 9 100

100

90

80

70

60

0

10

20

30

40

50

Years from randomisation

Dis

ea

se-f

ree

su

rviv

al

(%)

N EventsHR

(vs obs.)95% CI p value

Observation 1697 608

1 year 1702 505 0.76 (0.68–0.86) <0.0001

83.4%

81.3%

75.2%

Trastuzumab 1 year Trastuzumab 2 yearsObservation only

No. at risk

Observation only 1697 1201 1095 946 831

Trastuzumab 1

year1702 1319 1213 1099 996

2 years 1700 518 0.77 (0.69–0.87) <0.0001

Trastuzumab 2

years1700 1361 1222 1087 965

•No added benefit for 2 years

•Independent of ER status

•Higher cardiac toxicity for 2 years

PHARE failed to show non-inferiority of

6 months vs. 1 year of trastuzumab treatment

Pivot X, et al. Lancet Oncol 2013

0

25

50

75

100

DFS

(%

)

0 12 24 36 48 60Months

Events 2-yr DFS (95% CI) HR (95% CI) P value

Trastuzumab 1 yr 175 93.8% (92.6–94.9)

Trastuzumab 6 mo 219 91.1% (89.7–92.4) 1.28 (1.05, 1.56) 0.29

42.5 months’ MFU

Short-HER: Study Design

Anders ASCO 2017

Stratification factors: HR status, Nodal status

Radiotherapy and hormonal therapy started at the completion of ChemoRx, when indicated

EUDRACT number: 2007-004326-25

NCI ClinicalTrials.gov number: NCT00629278

Non-inferiority study: HR = 1.29,

Alpha: 0.05 (one tail) Power: 80%

n = 1250 pts

SHORTHer Primary Objective of DFS

5.2 yrs Follow-upN = 1253

0.0

00

.25

0.5

00

.75

1.0

0

626 601 576 554 476 351 233 120 46B short627 608 592 566 482 374 239 132 43A long

Number at risk

0 12 24 36 48 60 72 84 96Months from randomization

A long B short

HR = 1.15 (0.91 – 1.46); 0.78 probability5yr DFS (87.5% LONG vs. 85.4% SHORT)

Subset Analyses:

HR>1.0 favors LONG

Ratio of HRs

(90%CI)

p-value

Stage

III vs I+II

2.30

(1.35, 3.94) < 0.001

Nodal status

N2+N3 vs N0+N1

2.25

(1.33, 3.83) < 0.001

No difference in 5 yr OS (95.1 vs 95%)

Anders ASCO 2017

ShortHER: Cardiac Adverse Events

Long

N=627

Short

N=626

Grade N(%) N(%)

2 69 (11.0) 22 (3.5)

3 12 (1.9) 5 (0.8)

4 1 (0.2) 0

Total 82 (13.1) 27 (4.3)P<0.0001p<0.0001

HR= 0.32 (95% CI 0.21;0.50) p<0.0001

Anders ASCO 2017

TAKE HOME MESSAGES

Duration of adjuvant trastuzumab: DON’T CHANGE YOUR PRACTICE

In total about 15.000 pts enrolled to answer duration question!

Need to identify biomarkers to allow to identify de-escalate!

(Aleix Prat ASCO 2018, Her2 Enriched)

Duration of adjuvant trastuzumab: STORY NOT FINISHED

Tolaney ASCO 2017

Risk of Disease Recurrence at 5 yrs

• Definitions vary

• With these caveats, without treatment

Tolaney ASCO 2017

T1a 2 – 10%

T1b 5 – 20 %

T1c 10 – 25%

APT (Tolaney) trial: Adjuvant paclitaxel and trastuzumab

for low-risk HER2-positive breast cancer

Tolaney NEJM 2015

* Loading dose of 4 mg/kg IV trastuzumab on Day 1;† Radiation and hormonal therapy was initiated after completion of paclitaxel;‡ Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks; qxw, every x weeks.ER, oestrogen receptor

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

Paclitaxel (80 mg/m2) + trastuzumab

(2 mg/kg) x 12 weeks (q1w)*†

N = 406

• HER2-positive

• ER+ or ER–

• Node-

negative

tumour ≤3 cm

Primary

endpoint:

Invasive DFS

HH H H H H H H H H H H H

Q3w doses of trastuzumab (6 mg/kg) x 13‡

Total 18 cycles of trastuzumab

NOTE: This is a single-arm, single-centre study, so is unable to provide definitive data on treatment benefit

APT Trial

7 year Update ASCO 2017

Tolaney SM et al. Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC).

Poster discussion at ASCO 2017, 2–6 June, Chicago, IL, USA (Abstract 511).

APT (Tolaney) trial: IDFS rates in small,

node-negative tumours

Tolaney SM, et al. ASCO 2017 (Abstract 511).PR, progesterone receptor

Jones Lancet Oncol 2013

Docetaxel/Cyclophosphamide/Trastuzumab

for Early Stage HER2+ Cancers

Stage I – II

HER2-positive

Early breast cancer

Docetaxel/Cyclophosphamide/

TrastuzumabTrastuzumabX

4

ATEMPT Trial Schema

Presented By Sara Tolaney at 2017 ASCO Annual Meeting

International guidelines recommend the APT treatment regimen in patients with small, node-negative tumours

1. Curigliano G, et al. Ann Oncol 2017; 28:1700–1712;2. Senkus E, et al. Ann Oncol 2015; 26(Suppl 5): v8–v30.

* Level of evidence I: Evidence from at least one large, randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted, randomised trials without heterogeneity; Grade of recommendation A: strong evidence for efficacy with a substantial clinical benefit, strongly recommended.

Adjuvant systemic treatment2

Luminal B HER2-positive tumours are treatedwith chemotherapy, endocrine therapy and trastuzumab[I, A].* No randomised data exist to support omission of chemotherapy in this group. However, in small, node-negative tumours, combination of single-agent paclitaxel and trastuzumab provides excellent results.

Adjuvant therapy: HER2 targeted therapy1

Paclitaxel and trastuzumab is an effective regimen for stage I breast cancers with low rates of recurrence.

St. Gallen ExpertConsensus

Primary Breast CancerClinical Practice Guidelines

Adjuvant Therapy For Stage 1 HER2+ Disease

Presented By Eric Winer at 2014 ASCO Annual Meeting

• Increased rates of BCS and fewer mastectomies1–4

• Smaller patient population required and more rapid results:5 new therapies available to

patients quicker

• Assessment of pCR allows early evaluation of therapeutic effect4

– pCR predictive of survival benefit4,6

• Comparable survival benefit1,2

Advantages of neoadjuvant over adjuvant therapy

in breast cancer

1. Fisher B, et al. J Clin Oncol 1997; 15:2483–2493;2. Wolmark N, et al. J Natl Cancer Inst Monogr 2001; (30):96–102;

3. Kaufmann M, et al. Ann Surg Oncol 2012; 19:1508–1516;4. Kaufmann M, et al. J Clin Oncol 2006; 24:1940‒1949;

5. Amos KD, et al. Int J Breast Cancer 2012; 2012:385978;6. Buzdar AU. Cancer 2007; 110:2394–2407.

Surgery RelapseSystemic therapy

Systemic therapy Surgery pCR

Adjuvant trial:

Neoadjuvant trial:

Weeks

Years

BCS, breast-conserving surgery; pCR, pathological complete response.

n = 364

n = 471

50‡

31‡

Chemotherapy+H

Chemotherapy(hormone receptor-negative)

p = not reported

n = 385

n = 701

CTNeoBC

meta-analysis5

30‡

18‡

Chemotherapy+H

Chemotherapy(hormone receptor-positive)

p = not reported

Impact on pCR rates from the addition of trastuzumab to

neoadjuvant chemotherapy in patients with

HER2-positive EBC

* No evidence of residual invasive cancer, in breast or axilla† No evidence of residual disease in breast tissue‡ Absence of invasive cancer in the breast and axillary nodes; absence of DCIS/absence of invasive cancer in the breast and axillary nodes;DCIS allowed/absence of invasive cancer in the breast and DCIS allowed; regardless of nodal involvementDCIS, ductal carcinoma in situ; FEC, 5-fluorouracil+epirubicin+cyclophosphamide; EC, epirubicin+cyclophosphamide; X, capecitabine.

1. Buzdar AU, et al. Clin Cancer Res 2007; 13:228−233;2. Gianni L, et al. Lancet 2010; 375:377−384;

3. Untch M, et al. J Clin Oncol 2010; 28:2024−2031;4. Loibl S, et al. SABCS 2011 (Abstract S5-4; oral presentation);

5. Cortazar P, et al. SABCS 2012 (Abstract S1-11; oral presentation.

n = 662

n = 665

n = 1050

n = 118

n = 19

n = 445

n = 117

n = 45

16*

22†

26*

32*

43†

60*

GeparQuattro3

NOAH2

MD Anderson1

pCR (%)

German trials

meta-analysis4

T�FEC

H+(T�FEC)

AC�T�CMF

H+(AC�T�CMF)

H+(EC�T([X]) EC�T�X

(HER2-negative)

27*

18*

Chemotherapy+H

Chemotherapy

p < 0.0007

p = not reported

0 20 40 60

p = not reported

p = not reported

FDA CT NeoBC Meta-analysisThere was no correlation between

magnitude of pCR difference and EFS/OS

It can not be considered a surrogate endpoint

Cortazar P, Zhang L, et al. Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC).

Cancer Res December 15, 2012; 72 (24 Supplement): S1-11.

Summary

• Is pCR a relevant surrogate endpoint for

patients receiving anti-Her2 Therapy?

– pCR is associated with an improved event free

survival (EFS) for patients receiving neoadjuvant

trastuzumab

– There is a stronger association for ER-ve/Her2

positive patients

– However, it can not be considered as a surrogate

endpoint for EFS or OS.

TAKE HOME MESSAGE

If CT is needed, use the neoadjuvant setting

Dual Anti Her 2 neoadjuvant trialsKey differences in design

• Inclusion of IBC/LABC

• Definition of pCR

• Choice of chemo backbone

• Duration of targeted therapy

• Completion of protocol specified therapy

• Sample Size

Trastuzumab

Lapatinib

NeoALTTO Study DesignNeoALTTO Study Design

Baselga J, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-3.

• Invasive operable HER2+ BC

• T >2 cm (inflammatory BC excluded)

• LVEF ≥50%

N = 450

RANDOMIZE

SURGERY

Lapatinib

Trastuzumab

Lapatinib

Paclitaxel

Paclitaxel

Trastuzumab

Paclitaxel

6 wks +12 wks

FEC

X

3

Lapatinib

Trastuzumab

52 weeks of anti-HER2 therapy

34 wks

Stratification•T≤5 cm vs T>5 cm•ER or PgR+ vs ER & PgR-•N0-1 vs N≥2•Conservative surgery or not

IBC exclusion criteria

NeoALTTO: Overall Clinical Responseat 6 weeks (w/o chemo) and at surgery

NeoALTTO: Overall Clinical Responseat 6 weeks (w/o chemo) and at surgery

L = lapatinib; T = trastuzumab

At Week 6 (w/o chemo) At surgery

LN = 154

TN = 149

L+TN = 152

LN = 154

TN = 149

L+TN = 152

P<.001

P<.001P = .49

P = .049

Baselga J, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-3.

Overall Survival Analysis by treatment arm

Tests for interaction:

L + T vs T x HR p= 0.45

L vs T x HR p=0.72

Results of first analysis of EFS/OS are shown in square brackets

to provide comparison with this update

De Azambuja et al. Lancet Oncol 2014

Ove

rall

surv

iva

l

NeoALTTO trial

MEDIAN FU: 6.7 yearsJens Huober et al, ESMO 2017

Landmark Analysis: OS by PCR

Tests for interaction: pCR x HR p=0.33

Results of first analysis of EFS/OS are shown in square brackets

to provide comparison with this update

De Azambuja et al. Lancet Oncol 2014

Ove

rall

surv

iva

lO

vera

ll su

rviv

al

NeoALTTO trial

MEDIAN FU: 6.7 yearsJens Huober et al, ESMO 2017

NSABP B-41 Schema

OperableBreast Cancer HER-2 neuPositive

R

AC → WP+T

AC → WP+L

AC → WP+T+L

SURGERY

Tissue for Biomarkers

Trastuzumab for a total of

1 year

WP=Weekly Paclitaxel

Tissue for Biomarkers

Accrued 529 patients from July 16, 2007 to June 30, 2011

NSABP B-41pCR Breast by Hormone Receptor Status

N=100N=122 N=108 N=71N=55 N=63

HR+ HR–

P=0.23

P=0.96

P=0.49

P=0.71

Robidoux A, et al. Lancet Oncology 2013;14:1183-1192

NSABP B-41Overall Survival

N Events HR (vs. T) P (vs. T)

AC��WP+T 179 10 1 N/A

AC��WP+L 171 17 1.52 (0.69, 3.35) 0.11

AC��WP+T+L 172 7 0.63 (0.24, 1.67) 0.55

# At Risk

AC��WP+T 179 177 173 172 160 102

AC��WP+L 171 169 163 155 143 81

AC��WP+T+L 172 169 165 163 152 94

Overall log-rank test: P=0.07

Time in Years

Overa

ll S

urv

ival

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0 95.7%

94.5%89.4%

ALTTO trial

Presented by:

DISEASE-FREE SURVIVAL (DFS) ANALYSIS

ALTTO investigators

*Bracketed data in all KM

curves represent results of

the Primary Analysis –

ASCO 2014

*

A. Moreno-Aspitia et al, ASCO 2017

ALTTO study: Adjuvant lapatinib

and trastuzumab

Piccart-Gebhart M, et al. Adjuvant Lapatinib and Trastuzumab for Early HumanEpidermal Growth Factor Receptor 2–Positive Breast Cancer: Results From the Randomized Phase III

Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol 2016; 34:1034–1042.p ≤ 0.025 required for statistical significance.

Slide 32

pCR by Tumor and Microenvironmental Variables

Presented By Lisa Carey at 2018 ASCO Annual Meeting

NeoSphere Study DesignNeoSphere Study DesignTH (n = 107)docetaxel +trastuzumab

Gianni L, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-2.

BC, breast cancer; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel*Locally advanced = T2-3, N2-3, M0 or T4a-c, any N, M0; operable = T2-3, N0-1, M0; inflammatory = T4d, any N, M0

THP (n = 107)docetaxel +trastuzumab +pertuzumab

HP (n = 107)trastuzumab +pertuzumab

TP (n = 96)docetaxel +pertuzumab

S

U

R

G

E

R

Y

Patients with

operable or

locally advanced/

inflammatory*

HER2-positive

breast cancer

Chemo-naïve

and primary

tumors >2 cm

(N = 417)

FEC q3w x 3

Trastuzumab q3w cycles 5-17

FEC q3 x 3


Docetaxel q3w x 4→→→→FEC q3w x 3


FEC q3w x 3


Study dosing: q3w x 4

NeoSphere: pCR Rates (ITT Population)NeoSphere: pCR Rates (ITT Population)

CI, confidence interval; H, trastuzumab; P, pertuzumab; pCR, pathologic complete response; T, docetaxel

Gianni L, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-2.

P = .0198

P = .0141 P = .003

pC

R,

% ±± ±±

95%

CI

Long term outcome (EFS): NeoSPHERE

THP (86%)

HP (73%)

TH (81%)

TP (73%)

Gianni, Lancet Oncol 2016

Neoadjuvant pertuzumab added to TH

PFS

, %

EFS HR in ER- = 0.60

EFS HR in ER+ = 0.86

• Multicenter, randomized phase III study in the Netherlands

• Primary endpoint: pCR (ypT0/is, ypN0) by local assessment

• Secondary endpoints: RFS, BCSS, OS, toxicity

TRAIN-2: Study Design

Stratified by cT (0-2 vs 3-4), cN (neg vs pos), ER (neg vs pos), and age (< 50 vs ≥ 50 yrs)

van Ramshorst MS, et al. Lancet Oncol 2018

*21-day cycles: PTC + pertuzumab Day 1, P Day 8; paclitaxel 80 mg/m2, carboplatin AUC 6 mg.min/mL†21-day cycles. 5-fluorouracil 500 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 500 mg/m2. Trastuzumab 6 mg/kg with 8-mg/kg loading dose, pertuzumab 420 mg with 840-mg loading dose. ‡To complete 1 yr of adjuvant trastuzumab; endocrine therapy for ER+ and/or PgR+ tumors.

FEC-T † +

Pertuzumab Q3W

(n = 219)

3 cycles 6 cycles

Treatment-naive pts with HER2-

positive, stage II-III breast

cancer and LVEF ≥ 50%

(N = 438) PTC* +

Pertuzumab Q3W

(n = 219)

Surgery + adjuvant

therapy‡9 cycles

PTC* + Pertuzumab Q3W

(n = 219)

TRAIN-2: pCR

0

20

40

60

80

100

pC

R r

ate

(yp

TO

/is, yp

NO

), %

FEC-T + Pertuzumab

PTC + Pertuzumab

ER- and PR-All Pts ER+ and/or PgR+

67% 68%

89% 84%

51%55%

P = .75

P = .51

P = .61

P value for interaction .32

van Ramshorst MS, et al. Lancet Oncol 2018

NEOADJUVANT TRIALS OF DUAL BLOCKADE

TAKE HOME MESSAGES

• Dual blockage beneficial particularly in ER negative

disease, in terms of pCR rates

– Anthracycline-free options but in whom ?

• Interesting RR of 2 anti-HER-2 agents alone (with no CT)

• Benefit in long term outcome NOT FULLY CONFIRMED IN

THE LARGE ADJUVANT TRIALS

52The slides are the property of BIG. Permission required for reuse


APHINITY: Trial Design

Chemotherapy* + trastuzumab

+ placebo

Chemotherapy* + trastuzumab

+ pertuzumab

Randomisation and treatmentwithin 8 weeks of surgery

Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

Central

confirmation

of HER2 status

(N = 4805)

F

O

L

L

O

W

-U

P

10

Y

E

A

R

S

R

S

U

R

G

E

R

Y

*A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed

G. von Minckwitz et al, ASCO 2017, NEJM 2017


APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival

Number needed to treat: 112

expected: 89.2%

G. von Minckwitz et al, ASCO 2017, NEJM 2017

APHINITY trial

APHINITY: Study Design

� International, randomized, double-blind, placebo-controlled phase III trial[1]

� Primary endpoint: IDFS per modified STEEP definition[2] (excludes second primary non-BC as event)

� Secondary endpoints: IDFS per STEEP definition,[2] OS, distant recurrence-free survival, DFS, recurrence-free interval, safety, cardiac safety, health-related QoL

1. von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.

2. Hudis CA, et al. J Clin Oncol. 2007;25:2127-2132.

Patients with HER2+ EBC, no

prior invasive BC or anticancer

tx or RT, N+ any tumor size

(no T0) or N0 tumor size

> 1 cm,* BL LVEF ≥ 55%

(N = 4805)

Pertuzumab + Trastuzumab + CT†

(n = 2400)

Placebo + Trastuzumab + CT†

(n = 2405)

10-yr follow-upSurgery

Wk 52

*Or node negative with tumors > 0.5 to ≤ 1 cm + at least 1 of following: histologic/nuclear grade 3; ER negative and PgR negative;

aged < 35 yrs. Node-negative enrollment capped after first 3655 patients randomized. †Tx initiated ≤ 8 wks post surgery. Permitted CT: standard

anthracycline or nonanthracycline regimens. Endocrine and/or radiotherapy could be started at end of adjuvant CT.

APHINITY: IDFS by Nodal Status

von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.

Node Positive Node Negative

Mos

IDFS

(%

)

Pertuzumab (n = 897), 32 events

Placebo (n = 902), 29 events

Unstratified HR: 1.13 (95% CI: 0.68-1.86;

P = .064)

100

80

60

40

20

0480 6 12 18 24 30 36 42

99.7

99.5

99.1 98.4

99.0 97.5 96.2

96.7

IDFS

(%

)




P = .02)

100

80

60

40

20

0480 6 12 18 24 30 36 42

98.1

98.2

94.9 92.0

93.7 90.2 86.7

89.9

Mos

IDFS

(%

)




P = .277)

100

80

60

40

20

0480 6 12 18 24 30 36 42

98.9

99.3

96.5 94.8

96.8 94.4 91.6

93.0

Mos

APHINITY: IDFS by Hormone Receptor Status

von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.

Mos

IDFS

(%

)




P = .085)

100

80

60

40

20

0480 6 12 18 24 30 36 42

98.1

97.9

96.2 92.8

93.7 91.2 88.7

91.0

Hormone Receptor Positive Hormone Receptor Negative

Slide credit: clinicaloptions.com

APHINITY: IDFS in subgroup with

HR-negative disease

von Minckwitz G, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-PositiveBreast Cancer. N Engl J Med 2017; 377:122–131 (supplementary information).

A. Hormone receptor-negative

How do NNTs for DFS in the APHINITY

trial compare with other trials?

1. Jackisch C et al. SABCS 2015 (Abstract PD5-01); 2. Slamon D, et al. NEJM 2011; 365:1273–1283; 3. Slamon D, et al. SABCS 2015;

4. Perez EH, et al. JCO 2011; 29:3366–3373; 9. Perez EH, et al. JCO 2014; 32:3744–3752;

6. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.

HERA1 BCIRG-0062,3Joint

analysis4

,5

APHINIT

Y6

Study arm H TCH AC-TH AC-THPH +

chemo

ComparatorObservati

onAC-T AC-T H + chemo

NNTs for DFS

2 years – 20 17 18 143

3 years 17 17 15 12 112

4 years – 17 13 9 59

5 years 17 17 12 – –

8 years 17 – – – –

10 years 17 20 15 9 –

Interim OS results are still immature and have not yet

reached statistical significance

Strata: nodal status and protocol version, intended adjuvant chemotherapy regimen and central hormone receptor status

Hazard ratios were estimated by Cox regression

NOTE: The adjusted two-sided significance level for the first interim analysis of OS is <0.00001

von Minckwitz G, et al. N Engl J Med 2017; 377:122–131

(and supplementary information).

PERJETA–

Herceptin

(n = 2400)

Placebo–

Herceptin

(n = 2404)

Stratified HR (95% CI) 0.89 (0.66, 1.21)

p value 0.4673

Median FU, months 45.4

97.7%

97.7%

3 years

0 6 12 18 24 30 36 42 48

Time (months)

Pro

po

rtio

n e

ve

nt-

fre

e

0.8

0.6

0.4

0.2

0.0

1.0

No. of patients at risk

2400 2324 2305 2282 2263 2231 2186 1744 901

2404 2350 2339 2318 2293 2262 2209 1747 905

$$$

ExteNET 5-Yr Update: Neratinib vs Placebo After

Adjuvant Trastuzumab in HER2+ EBC

� Primary endpoint: IDFS at 2 yrs

� Primary analysis of 2-yr IDFS rate: neratinib, 93.9%; placebo, 91.6% (HR: 0.67; 95% CI: 0.50-0.91; P = .0091)

Patients with HER2+ EBC (stage I-III);

adjuvant trastuzumab completed ≤ 2 yrs

before randomization*; N+/- disease or

residual disease after neoadjuvant therapy;

known ER and PgR status

(N = 2840)

Neratinib 240 mg/day PO

(n = 1420)

Placebo

(n = 1420)

1 yr

*Amendment in Feb 2010

restricted enrollment to

patients with N+ disease who

completed trastuzumab ≤ 1 yr

before randomization.

Stratified by hormone receptor status (ER+ and/or PgR+

vs ER- and PgR-), nodal status (0 vs 1-3 vs ≥ 4), adjuvant

trastuzumab regimen (sequential vs concurrent with CT)

Endocrine therapy given according to

local practice.

Chan A, et al. Lancet Oncol. 2016;17:367-377. Martin M, et al. Lancet Oncol. 2017;18:1688-1700. Slide credit: clinicaloptions.com

ExteNET: 5-Yr IDFS Analysis

Mos After Randomization

IDFS

(%

)

Patients at Risk, n

Neratinib

Placebo

HR: 0.73 (95% CI: 0.57-0.92; P = .0083)

1420

1420

1316

1354

1272

1298

1225

1248

1106

1142

978

1029

965

1011

949

991

938

978

920

958

88

5

92

7

100

90

70

60

80

50

40

30

20

10

0

Neratinib

Placebo

600 6 18 2412 30 36 42 48 54

97.9%

95.5%

94.3%

91.7%

92.2%

90.2%

91.2%

89.1% 87.7%

90.2%

Martin M, et al. Lancet Oncol. 2017;18:1688-1700. Slide credit: clinicaloptions.com

ExteNET: 5-Yr IDFS Analysis by Hormone Receptor Status


IDFS

(%

)

Patients at Risk, n

Hormone Receptor Positive Hormone Receptor Negative

HR: 0.95 (95% CI: 0.66-1.35)HR: 0.60 (95% CI: 0.43-0.83)

Neratinib

Placebo

816

815

757

779

731

750

705

719

642

647

571

581

565

567

558

556

554

551

544

542

523

525

600 6 12 18 24 30 36 42 48 54

100

9080706050

40302010

0

Neratinib

Placebo

98.1%

96.1%

95.4%

91.7%

93.6%

89.8% 88.5%

92.6%


IDFS

(%

)

Patients at Risk, n

Neratinib

Placebo

604

605

559

575

541

548

520

529

464

495

407

448

400

444

391

435

384

427

376

416

362

402

600 6 12 18 24 30 36 42 48 54

100908070

6050403020

100

Neratinib

Placebo

97.5%

94.7%

92.8%

91.8%

90.8%

90.4% 89.3%

89.9%88.9%

88.8%

Martin M, et al. Lancet Oncol. 2017;18:1688-1700. Slide credit: clinicaloptions.com

91.2%

86.8%

Considerations for Management of Neratinib-Induced

Diarrhea: Prophylaxis

Loperamide at First Dose of Neratinib

� Give patients instructions for use of loperamide (potential to adjust dose if constipation occurs)

� Add budesonide or colestipol to manage loperamide-refractory diarrhea

Neratinib Dose Modifications

Hold if grade 2 lasting ≥ 5 days or grade 3 lasting ≥ 2 days or any grade with

complicated features*

Time Loperamide Dose Dose Frequency

Wks 1-2 4 mg 3 times per day

Wks 3-8 4 mg 2 times per day

Wks 9+ 4 mgAs needed, no more

than 16 mg/dayResume neratinib

at same dose

Resume neratinib

at reduced dose

(200/160/120 mg/day)

Resolves to grade ≤ 1

in ≤ 7 days

Resolves to grade ≤ 1

in 8-21 days

*Includes dehydration, fever, hypotension, renal failure, or

grade 3/4 neutropenia.

Neratinib [package insert]. 2018. Slide credit: clinicaloptions.com

ADAPT HER2+ / HR+ TRIAL• International, prospective, randomized phase II trial

• Primary endpoint: pCR (no invasive carcinoma in breast/nodes)

• Secondary endpoints: dynamic testing evaluation, EFS, OS, safety

Pts with ER+ and/or PgR+,

HER2+, cT1c - cT4a-c, cN,

cM0 BC and adequate

organ function, LVEF ≥

50%, normal ECG

(N = 375)

T-DM1 3.6 mg/kg Q3W

(n = 119)

Trastuzumab 8 mg/kg loading

dose, then 6 mg/kg Q3W + ET*

(n = 129)

T-DM1 3.6 mg/kg Q3W + ET*

(n = 127)

1. Harbeck N, et al. SABCS 2015. Abstract S5-03.

2. Hofmann D, et al. Trials. 2013;14:261.

Surgery†

Wk 12

*Tamoxifen if premenopausal; aromatase inhibitor (of investigator’s choice) if postmenopausal.†Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pCR).

ADAPT Trial

Harbeck N, et al. SABCS 2015. Abstract S5-03.

• 12-wk T-DM1 increased pCR rate vs trastuzumab + ET in women

with HER2+/HR+ EBC

– 41% vs 15%, respectively (P < .001)

– Addition of ET to T-DM1 did not raise pCR rate

– Menopausal status had minimal bearing on results

• Tolerable safety profile with low toxicity

• Early response significantly associated with increased pCR rate

– Detectable after 3 wks

– Authors conclude further investigation of T-DM1 in pts with EBC

warranted

HER2+ /HR- disease

Dual HER2

blockade

+

taxane

62%

20

40

60

80

100

Dual HER2

blockade

alone

29%

Dual HER2

blockade

+

taxane

+

other agent

(anthrac.,

carbo)

73 - 80%

%

PCR

rates

Based on NeoSphere, NeoAltto, Tryphaena

Who are these patients

with HER2+ HR- disease

who perhaps do not

need chemo ?

Courtesy G. Curigliano

Nitz et al. Annals of Oncology Sep 2017

Evolving Standard of HER2 Treatment

More or Less

Slide 31

Presented By Lisa Carey at 2018 ASCO Annual Meeting

How are we going to get there?

Katherine: Study Schema

Presented By Sara Tolaney at 2017 ASCO Annual Meeting

SABCS in 9 days!!!

Documents

(NEO-)ADJUVANT THERAPY FOR HER-2+ BREAST CANCER · chemotherapy in this group. However, in small, node-negative tumours, combination of single-agent paclitaxel and trastuzumab provides